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Cardiotoxic Medications Echocardiography Conference January 2, 2008 Michael Chuang Cardiotoxicity Impairment of function Valvular disorders Infarction Arrhythmias Thrombophilia Cardiotoxic Drugs Anthracyclines Tyrosine kinase inhibitors Dopamine agonists Appetite suppressants Glucocorticoids Antifungals Herbals Thiazolidinediones NSAIDs – COX2 inhibitors Alkylating drugs Interferons TNF antagonists Antidepressants Antipsychotics Cardiotoxic Drugs Anthracyclines Tyrosine kinase inhibitors Dopamine agonists (anti-Parkinsonians) Appetite suppressants Thiazolidinediones NSAIDs – COX2 inhibitors Alkylating drugs Interferons TNF antagonists Antidepressants Antipsychotics Glucocorticoids Antifungals Herbals Anthracyclines: Background Purpose: anti-cancer, chemotherapy Therapeutic mechanism: insertion into DNA of replicating cells, → DNA fragmentation, decreased DNA, RNA and protein synthesis Toxicity via: free radicals, ↑ oxidative stress breast, soft tissue sarcoma, leukemia, lymphoma, childhood tumors Toxicity probably NOT via therapeutic mechanism Examples: doxorubicin (Adriamycin®), danorubicin (Cerubidine®), epirubicin (Pharmorubicin®), mitoxantrone (Novantrone® [anthracendione]) Anthracyclines: Clinical Manifestations Acute Toxicity: BNP elevation, ventricular dysfunction, EKG abnormalities, pericarditismyocarditis syndrome days to weeks transient, not dose related Early Toxicity: ventricular dysfunction, heart failure weeks to months dose-related Late Toxicity: ventricular dysfunction, heart failure years dose-related Anthracyclines: Incidence [1] Retrospective study: 3941 patients given doxorubicin Overall incidence of heart failure 2.2% strongly dose related Cumulative Dose <400 mg/m2 ~400 mg/m2 ~550 mg/m2 ~700 mg/m2 Heart Failure 0.14% 3% 7% 18% Von Hoff et al, Ann Intern Med 1979 Anthracyclines: Incidence [2] 630 patients receiving FAC (fluorouracil, doxorubicin, cyclophosphamide) and dexrazoxane for advanced breast cancer. Dose ≤400 mg/m2 ~500 mg/m2 ~550 mg/m2 ~700 mg/m2 %CHF 5% 16% 26% 48% Swain et al, Cancer 2003 Anthracyclines: Risk Factors and Modifiers Risk factors: cumulative dose, age, combination chemotherapy (e.g. cyclophosphamide, taxanes, trastuzumab), prior cardiac disease, mediastinal radiation, hypertension, female sex (pediatric patients only) Risk reduction via: dose minimization, continuous (vs. bolus) administration, liposomal formulation of anthracycline, dexrazaxone, βblockers, CCBs, ARBs Anthracyclines: Maximum “Safe” Doses Drug Dose doxorubicin 550 mg/m2 danorubicin 600 mg/m2 epirubicin 1000 mg/m2 idarubicin 100 mg/m2 Mitoxantrone 160 mg/m2 Anthracyclines: Assessment Biomarkers natriuretic peptides: ANP, BNP Troponin ECG: QRS duration, QTc, T-wave changes Endomyocardial biopsy Ejection Fraction Ventriculography Imaging Assessment of Cardiac Function Accuracy versus Reproducibility Modalities Radionuclide ventriculography (RVG, MUGA) Echocardiography Cardiovascular Magnetic Resonance (CMR) Computed Tomography (CT) Radionuclide Ventriculography Widely used in oncology trials Reproducibility good Injection of tagging agent Radiation expousre (~8 mSv) Computed Tomography Very fast Accurate* and reproducible Iodinated contrast agent Radiation exposure *Limited temporal resolution Echocardiography Noninvasive, generally well tolerated Patient-associated image quality limitations Assessement of valves, hemodynamics in addition to function Reproducibility of 2D echo limited compared with volumetric techniques 3D echo markedly improves reproducibility Improved Reproducibility of 3DE Hibberd et al, AHA 1996 Otterstad et al, Eur Heart J 1997 Coefficient of Variation, % 25 3D Intra 3D Inter 20 2D Intra 2D Inter 15 10 5 0 EDV ESV SV EF CMR Very accurate (probably) Reproducible Contraindications Local availablity and expertise Chuang et al, JACC 2000 Reproducibility Beware systematic differences between imaging methods and modalities Lack of mean bias does not guarantee detection of small changes Chuang et al, JACC 2000 Tyrosine Kinase Inhibitors: Background Purpose: anti-cancer, chemotherapy hematologic cancers, breast cancer, gastrointestinal stromal tumor (GIST) Therapeutic Mechanism: inhibition of dysregulated TKs causal/contributory to tumorigenesis Humanized monoclonal antibodies Small-molecule TKIs Cardiotoxicity: asymptomatic LV dysfunction, CHF Examples: trastuzumab (Herceptin®), sunitinib (Sutent®), imatinib (Gleevec®, Glivec®) Trastuzumab (Herceptin®) [1] Human epidermal growth factor (HER2, ERBB2) overexpressed in ~25% breast cancers, marker of poor prognosis Trastuzumab: humanized monoclonal antibody targeting ERBB2, often used in combination with taxanes Multiple randomized trials show trastuzumab benefit in ERBB2+ breast cancers, 80% of trials show cardiotoxicity Viani et al, BMC Cancer 2007 Trastuzumab (Herceptin®) [2] Aysmptomatic LV dysfunction: 4-17% Symptomatic CHF: up to 4.5% Mechanism unknown, but may include: Interaction with other chemotherapeutic agents Antibody-dependent cell-mediated cytotoxicity Downregulation/inhibition of ERBB2 signalling Trastuzumab (Herceptin®) [2.1] ERBB2 signalling mandatory for embryonic cardiomyocyte proliferation (germline deletion of ERBB2 fatal in mice) Late ERBB2 deletion → age-related DCM, impaired response to pressure overload Trastuzumab (Herceptin®) [2.2] ERBB2-binding triggers intracellular signalling Breast CA: inhibits autophosphorylation of ERBB2ERBB3 heterodimers Cardiomyocytes (rat): ↓ ERBB2 activatio n, ↓ BCL-XL , ↑ BCL-XS Release of cytochrome c, caspase activation Loss of mitochondrial membrane potential Reduction in ATP levels Contractile dysfunction Grazette et al, JACC 2004 Trastuzumab (Herceptin®) [2.3] Force et al, Nature Rev: Cancer 2007 Trastuzumab (Herceptin®) [2.2] ERBB2-binding triggers intracellular signalling Breast CA: inhibits autophosphorylation of ERBB2ERBB3 heterodimers Cardiomyocytes (rat): ↓ ERBB2 activation, ↓ BCL-XL , ↑ BCL-XS Release of cytochrome c, caspase activation Loss of mitochondrial membrane potential Reduction in ATP levels Contractile dysfunction Grazette, JACC 2004 Trastuzumab (Herceptin®) [2.4] Force et al, Nature Rev: Cancer 2007 Trastuzumab (Herceptin®) [2] Aysmptomatic LV dysfunction: 4-17% Symptomatic CHF: 1-3% Mechanism unknown: Interaction with other chemotherapeutic agents Antibody-dependent cell-mediated cytotoxicity Downregulation/inhibition of ERBB2 signalling Toxicity at least partially reversible Reversal after drug discontinuation Response to CHF medications Trastuzumab (Herceptin®) [3] Combination therapy and risk of CHF: Paclitaxel: 4.2% Paxlitaxel + trastuzumab: 8.8% Anthracycline: 9.6% Anthracycline + trastuzumab: 28% Decrease in EF ≥ 15%: ~5% of subjects, risk with prior anthracycline exposure 6-fold that of anthracycline-naïve Symptomatic dysfunction: 78% improved off drug 12% progressive HF Risk factors: prior/concommitant anthracycline exposure, pretreatment NYHA class Suter et al, Breast, 2004 Sunitinib (Sutent ®) Small-molecule multi targeted TKI VEGFR 1-3, PDGFRa,b, KIT, CSF-1, RET Inhibition of angiogenesis FDA and EU approved for GIST, renal-cell carcinoma Cardiotoxicity: GIST: no change in EF after 8 weeks [Demetri, Lancet 2006] Metastatic RCC: 10% had decrease in EF after 6 months, no clinical sequelae [Motzer, NEJM 2007] Pfizer insert: 11% of patients have decrease in EF to less than 50% Sunitinib: Study Design 75 adults with imatinib-resistant GIST Open-label Phase I/II trial of sunitinib at DFCI Cycle: 50 mg daily. 4 weeks on, 2 weeks off 4 cycles Serial EKG, biomarkers, radionuclide ventriculography (baseline EF > 50%) Interstudy reproducibility: 2-3% Sunitinib: CV Events - Definitions CHF: documented signs and symptoms, reduction in EF to < 50%, typical CXR and relief with CHF therapy MI: TnI>0.10 and clinical symptoms, EKG changes Death: cardiovascular vs. noncardiovascular, adjucated by cardiologists and oncologists; CV death only if concordance Sunitinib: CV Events Sunitinib: Maximum Decline in EF Sunitinib: Predicted Decrease in EF Sunitinib: Mitochondrial Abnormalities (rodent models) Sunitinib: Hypertension [1] Sunitinib: Hypertension [2] Sunitinib: Study Summary 11% of 75 patients had CV event 8% had NYHA Class III or IV HF ~50% developed hypertension EF declined after each cycle of treatment In mice: Increased mitochondrial damage No increase in cardiomyocyte apoptosis Sunitinib + phenylephrine (inducing HTN) increased apoptosis 7-fold vs phenylephrine alone Dopamine Agonists: Background [1] Purpose: anti-Parkinsonian, restless leg syndrome, hyperprolactinemia, Tourette’s syndrome Therapeutic mechanisms: stimulation of dopamine receptors Toxicity via: agonism of 5-HT2B receptors on cardiac valves → fibrosis, regurgitation Examples: pergolide (Permax®), cabergoline (Dostinex ®) Dopamine Agonists: Background [2] Ergot derivatives vs. non-ergot Ergot: pergolide, cabergoline Non-ergot: pramipexole, ropinrole Non-cardiac side effects: retroperitoneal and pleuropulmonary fibrosis Ergot Claviceps fungus, parasitic on many grains Overwinters as a sclerotium which contains alkaloids, e.g. ergotamine Effects include: Vasoconstriction – St. Anthony’s fire Uterine contractions Hallucinations Convulsions Death Ergot-Derived Dopamine Agonists [3] 155 patients on dopamine-agonist antiParkinsonians, 90 controls On treatment ≥ 12 months, no prior valve disease, no other drugs likely to cause valvulopathy Pergolide (n=64), cabergoline (49), nonergot (42) Transthoracic echo (Sequoia) Per-valve regurgitation graded 0-4 Composite valve score 0-12 Thickening defined as >5mm Mitral-valve tenting area Zanettini et al, NEJM 2007 Ergot-Derived Dopamine Agonists [4] Valvular abnormalities more prevalent in pergolide and cabergolide groups vs. controls and vs. non-ergot dopamine agonist treated Grade III and IV regurgitation Pergolide (23.4%) Cabergoline (28.6%) Controls (5.6%), non-ergot (0%) Valve thickening: Pergolide (n=17, 27%) Cabergoline (n=8, 16%) Control and non-ergot (0%) Zanettini et al, NEJM 2007 Ergot-Derived Dopamine Agonists [5] Relative Risk MR AR TR Pergolide 6.3 [1.4-28.3] 4.2 [1.2-15] Cabergoline 4.6 [0.9-22.8] 7.3 [2.2-24.8] 5.5 [0.6-51.6] Cumulative doses correlated with severity of regurgitation 5.6 [0.7-49] Pergolide: r=0.34, p=0.005 Cabergoline: r=0.26, r=0.06 Mitral-valve tenting > in treatment vs controls Tenting correlated with MR severity, p=0.001 Zanettini et al, NEJM 2007 Ergot-Derived Dopamine Agonists [6] Case-control (1:25) study UK GPRD data Aged 40-80 with ≥ 2 prescriptions btwn 1988-2005 No prior valve disease, murmurs, CHF, MI, carcinoid, other drugs assoc. with valve dz, IVDU 31 patients with new valve regurgitation Only 16 cases confirned by echo or cath Relative risk Pergolide 4.9 [1.5-15.6] Cabergoline 7.1 [2.3-22.3] Risk increased with cumulative dose/duration Schade et al, NEJM 2007 Ergot-derived dopamine agonists: Summary [7] Results consistent across multiple studies Risk of valve disease increases ~5-6 fold with pergolide or cabergoline Risk increases with dose, duration of exposure Susceptibility depends on individual factors Reversibility after drug discontinuation unknown Serial monitoring by echocardiography ? Anorectic Agents/Fenfluramine: Background Purpose: appetite suppression Therapeutic mechanisms: activation of serotonin release, inhibition of serotonin breakdown Toxicity via: increased serotonin levels, likely in combination with activation of 5-HT2B receptors Examples: fenfluramine (dexfenfluramine), phentermine Fenfluramine: Cardiac Effects Clinically-significant valvular regurgitation Mitral valve abnormalities Decreased posterior-leaflet mobility Anterior-leaflet thickening and diastolic doming Subvalvular disease (chordal shortening/thickening) Aortic regurgitation, leaflet thickening and retraction Pulmonary hypertension Fenfluramine [3] 24 women (44±8 years), 12±7 months after fenfluramine-phentermine therapy No history of CV disease Right and left-sided valvular lesions 5 went to surgery at press time 8 new cases of pulmonary hypertension Connolly et al, NEJM 1997 Fenfluramine: MV Gross Specimen [4] Connolly et al, NEJM 1997 Fenfluramine: Mitral Valve [5] Connolly et al, NEJM 1997 Fenfluramine: [6] Multisite reader-blinded controlled study 30 days of drug therapy within 14 months of enrollment 1473 patients, mean BMI 35±7 kg/m2 2D Echo on HP Sonos 2000 or 2500 systems Valvular regurgitation Valve leaflet thickness and mobility Gardin et al, JAMA 2000 Fenfluramine: [6] Treated patients had higher prevalence of AR Prevalence Relative Risk dexfenfluramine 8.9% 2.18 [1.32-3.59] dexfenfluramine / phentermine control 13.7% 3.34 [2.09-5.35] 4.1% - No difference in prevalence of MR (4.9, 5.1, 3.2%) No difference in valve mobility No difference in MI, CHF or serious arrhythmia Gardin et al, JAMA 2000 Fenfluramine: [7] 1-year follow up in 78% of subjects Interreader agreement for change in grade AR: 87.4%, k=0.63 MR: 57.1%, k=0.32 Intrareader agreement for change in grade AR: 96.5%, k=0.32 MR: 86.8%, k=0.30 Gardin et al, JAMA 2001 Fenfluramine: [8] Gardin et al, JAMA 2001 Fenfluramine: [9] Multiple studies suggest that after drug discontinuation: Progression of valve disease is rare Regression of disease is possible Davidoff et al, Arch Intern Med 2001 Mast et al, Ann Intern Med 2001 Weissman et al, Ann Intern Med 2001